The Role of Neurogenesis and APP in Alzheimer’s Disease

New Insights into Human Neurogenesis and Alzheimer’s Disease

A recent study conducted by researchers at the Paris Brain Institute has shed light on the process of neurogenesis, which involves the formation of neural cells from stem cells in humans. This groundbreaking research suggests that the timing of neurogenesis may be linked to the development of neurodegenerative diseases like Alzheimer’s. Specifically, the study indicates that abnormalities in the expression of the amyloid precursor protein (APP) could result in a normally functioning brain at birth but increased susceptibility to neurodegeneration later in life.

Amyloid Precursor Protein’s Influence on Human Brain Development

The research conducted at the Paris Brain Institute has revealed a significant role played by the amyloid precursor protein (APP) in regulating the development of the human brain. APP, commonly associated with Alzheimer’s disease, has been found to influence the timing of neurogenesis. The absence of APP leads to accelerated production of neurons, suggesting a potential connection between the timing of neurogenesis and the onset of neurodegenerative diseases. These findings suggest that early vulnerabilities during neurogenesis may contribute to neurodegeneration later in life.

Understanding Neurogenesis in Humans

Neurogenesis, the process of neural cell formation from stem cells, begins in the fetus around 5 weeks gestation and is nearly complete by 28 weeks in the cerebral cortex. This intricate process involves finely tuned mechanisms.

According to Khadijeh Shabani, a post-doctoral researcher at the Paris Brain Institute, neurogenesis in humans lasts longer compared to other species. Neural stem cells remain in a progenitor state for an extended period before differentiating into glial cells, astrocytes, or oligodendrocytes, which form the brain and spinal cord’s architecture.

Unveiling the Role of APP in Neuronal Production

The researchers focused on investigating the amyloid precursor protein (APP), which is expressed throughout the nervous system’s development. Bassem Hassan, the leader of the “Brain Development” team at the Paris Brain Institute, states that APP is an intriguing research target due to its fragmentation, which produces amyloid peptides. These peptides are associated with the toxic aggregation observed in Alzheimer’s disease and suggest that APP may play a central role in the disease’s early stages.

APP is known to be involved in various biological processes in many species, such as cerebral lesion repair, cellular response orchestration after oxygen deprivation, and brain plasticity regulation. In the case of human neurogenesis, APP’s expression is particularly significant during the differentiation and migration of cortical neurons. The researchers used cell sequencing data and the CRISPR-Cas9 technique to study APP’s role in human brain development. They found that APP regulates the timing of neurogenesis by influencing two finely tuned genetic mechanisms: stem cell proliferation control and the activation of new neuron production.

Unique Characteristics of Human Neurogenesis

Unlike in rodents, the loss of APP significantly accelerates brain neurogenesis in humans. This discrepancy suggests that APP’s regulatory role is negligible in mice but essential for the neurodevelopment of humans. The human brain requires the generation of a large number of neurons over an extended period to achieve its final form. Any abnormalities related to APP could lead to premature neurogenesis and significant cellular stress. These consequences may manifest later in life, particularly in the brain regions where early signs of Alzheimer’s disease are observed, which also undergo the longest maturation during childhood and adolescence.

The Link Between Neurogenesis Timing and Neurodegeneration

Is there a direct link between the timing of neurogenesis and the mechanisms underlying neurodegeneration? While neurodegenerative diseases are typically diagnosed between the ages of 40 and 60, clinical signs often appear decades after the initial decline in certain neuronal connections. This loss of connectivity may indicate molecular anomalies present since childhood or even earlier.

Further research is necessary to confirm whether APP plays a central role in the neurodevelopmental disruptions that contribute to the onset of Alzheimer’s disease. If so, it could be considered that these disruptions lead to the formation of a brain that initially functions normally but becomes particularly vulnerable to biological events (such as inflammation, excitotoxicity, or somatic mutations) and environmental factors (such as poor diet, lack of sleep, or infections). Over time, these stresses may contribute to neurodegeneration, a phenomenon specific to the human species that becomes more apparent with increasing life expectancy.

Reference: “The temporal balance between self-renewal and differentiation of human neural stem cells requires the amyloid precursor protein” by Khadijeh Shabani, Julien Pigeon, Marwan Benaissa Touil Zariouh, Tengyuan Liu, Azadeh Saffarian, Jun Komatsu, Elise Liu, Natasha Danda, Mathilde Becmeur-Lefebvre, Ridha Limame, Delphine Bohl, Carlos Parras, and Bassem A. Hassan, 16 June 2023, Science Advances.
DOI: 10.1126/sciadv.add5002

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More about neurogenesis timing

• “Neurogenesis and Alzheimer’s Disease: Understanding the Link”
• “Role of Amyloid Precursor Protein in Human Brain Development”
• “Neurodevelopmental Disruptions and Vulnerabilities to Neurodegenerative Diseases”